The proposed project will examine the hypothesis that abnormalities in membrane composition and function (a) are present in some if not all psychotic disorders, (b) can be used to discriminate lithium-responsive and non-responsive illnesses, and (c) can be used to discriminate the various subgroups of lithium-responsive illnesses. Work from our laboratory has shown that there is a good-prognosis form of schizophrenia which like most manic-depressive illnesses, is lithium responsive. We will compare and contract various membrane parameters in lithium responsive bipolar and good prognosis patients in order to determine which factors are associated with a positive lithium response. These data will be compared to results obtained from normal controls, hospitalized personality disorder patients and patients with non-lithium responsive schizophrenia. The membrane parameters to be examined are (a) membrane lipid composition, (b) membrane fluidity, (c) Na+ Li+ counterflow and lithium passive leak, (d) Na+, K+ ATPase activity, (e) phosphoinositide metabolism and (f) phospholipid methylation. Our preliminary results have shown that in the erythrocyte ghost membranes of the lithium-responsive good prognosis patients there is a deficiency of phosphatidylcholine (PC). We hypothesize that lithium might stimulate phospholipid methylation in order to correct this decrement and indeed we have observed that lmM lithium stimulates methylation in such patients. In contrast lithium inhibits methylation in normal controls and chronic schizophrenics. We now propose to extend these findings. We will examine in both lithium responsive and non-responsive groups the following parameters: (a) baseline methylation activity in both erythrocyte ghost and platelet plasma membranes, (b) the effects of invitro additions of lithium on methylation in these preparations, (c) the relationship among baseline and lithium-altered methylation and membrane lipid composition and (d) the effects in lithium-responsive/non-responsive patients of chronic lithium administration on these parameters (a-c). Overall, the proposed project will provide significant new insight into a biochemical nosology for lithium responsive illnesses and new information into the mechanisms of lithium action.